In Project 1, Drs. Brown, Tamimi, and co-investigators seek to gain a better understanding of the role of the androgen receptor (AR) in cancer risk and progression. Although the androgen receptor (AR) is expressed in normal breast epithelial cells and in 60-70% of breast tumors, remarkably little is known about the potential role of androgens in normal or malignant breast tissue. Previous studies examining AR signaling and breast cancer prognosis have been limited in sample sizes, focused solely on AR status, and have taken into account very few other prognostic and treatment factors. To explore this clinically challenging issue, this population based study combines the valuable resources of the Nurses Health Study (NHS) and the adjuvant Breast International Group 1-98 (BIG 1-98) endocrine therapy trial, with a collaborative team of established investigators in epidemiology, pathology and molecular biology in the field of AR signaling and breast cancer. They will also seek to establish an AR profile in addition to single marker AR testing in normal breast tissue utilizing methods they have established to identify the target genes and collaborating transcription factors for steroid receptors. This signature will be used to assess the risk of breast cancer development using tissue from the benign breast disease nested case-control study and the ongoing NHS cohort. Their proposed comprehensive assessment of AR signaling and the elucidation of the effects of AR signaling on breast cancer risk will integrate state-of-the-art functional epigenetics approaches such as ChIP-seq to dissect the role of AR signaling breast cancer risk, and would allow for the stratification of interventional strategies in women with different AR signaling. In addition, they will examine lifestyle factors that may modify breast cancer survival according to AR status. This will provide insight into underlying mechanisms of AR signaling on breast cancer development and progression, and may identify a subgroup of breast cancer survivors most likely to benefit from modifying their behaviors such as increasing physical activity levels. Identifying lifestyle factors that improve the survival among women with breast cancer has important public health implications and may provide women with additional motivation to make lifestyle changes that may alter the androgen signaling and hence their risk of breast cancer. Preliminary work from Project 1 investigators and other published studies demonstrate that for breast cancer outcomes, the role of AR is dependent on subtype. They will build on these results to translate AR into a predictive biomarker for response to subtype-specific therapies and a potential therapeutic target. The development of an AR target gene set specific to the different breast cancer subtypes is a novel strategy in this proposal and may explain the different prognosis associated with AR expression in breast cancer. The study of AR signaling on treatment outcomes in these breast cancer subtypes has important clinical implications and the potential for opportunities to translate their findings into clinical practice by identifying the clinical scenarios in which modulation of AR would have a desirable effect.